title: Globin-coupled heme containing oxygen sensor soluble adenylate cyclase in Leishmania prevents cell death during hypoxia.
abstract: Globin and adenylate cyclase play individually numerous crucial roles in eukaryotic organisms. Comparison of the amino acid sequences of globins and adenylate cyclase from prokaryotic to eukaryotic organisms suggests that they share an early common ancestor, even though these proteins execute different functions in these two kingdoms. The latest studies of biological signaling molecules in both prokaryotic and eukaryotic organisms have discovered a new class of heme-containing proteins that act as sensors. The protein of the globin family is still unknown in the trypanosomatid parasites, Trypanosome and Leishmania. In addition, globin-coupled heme containing adenylate cyclase is undescribed in the literature. Here we report a globin-coupled heme containing adenylate cyclase (HemAC-Lm) in the unicellular eukaryotic organism Leishmania. The protein exhibits spectral properties similar to neuroglobin and cytoglobin. Localization studies and activity measurements demonstrate that the protein is present in cytosol and oxygen directly stimulates adenylate cyclase activity in vivo and in vitro. Gene knockdown and overexpression studies suggest that O2-dependent cAMP signaling via protein kinase A plays a fundamental role in cell survival through suppression of oxidative stress under hypoxia. In addition, the enzyme-dependent cAMP generation shows a stimulatory as well as inhibitory role in cell proliferation of Leishmania promastigotes during normoxia. Our work begins to clarify how O2-dependent cAMP generation by adenylate cyclase is likely to function in cellular adaptability under various O2 tensions.
authors.affiliation: Division of Structural Biology and Bio-Informatics, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology, Kolkata 700032, India.
authors.forename: Sumit
authors.initials: S
authors.lastname: Sen Santara
authors.forename: Jayasree
authors.initials: J
authors.lastname: Roy
authors.forename: Supratim
authors.initials: S
authors.lastname: Mukherjee
authors.forename: Moumita
authors.initials: M
authors.lastname: Bose
authors.forename: Rina
authors.initials: R
authors.lastname: Saha
authors.forename: Subrata
authors.initials: S
authors.lastname: Adak
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology*; D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism*; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism; D006418:Heme / Q000235:genetics / Q000378:metabolism*; D018320:Leishmania major / Q000235:genetics / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism*; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D015800:Protozoan Proteins; D006418:Heme; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D010100:Oxygen